title: Widespread increase in myeloid calcifying cells contributes to ectopic vascular calcification in type 2 diabetes.
abstract: BACKGROUND
  Acquisition of a procalcific phenotype by resident or circulating cells is important for calcification of atherosclerotic plaques, which is common in diabetes.
  
  
  OBJECTIVE
  We aim to identify and characterize circulating calcifying cells, and to delineate a pathophysiological role for these cells in type 2 diabetes.
  
  
  RESULTS
  We demonstrate for the first time that a distinct subpopulation of circulating cells expressing osteocalcin and bone alkaline phosphatase (OC(+)BAP(+)) has procalcific activity in vitro and in vivo. The study of naïve patients with chronic myeloid leukemia indicated that OC(+)BAP(+) cells have a myeloid origin. Myeloid calcifying OC(+)BAP(+) cells (MCCs) could be differentiated from peripheral blood mononuclear cells, and generation of MCCs was closely associated with expression of the osteogenic transcription factor Runx2. In gender-mismatched bone marrow-transplanted humans, circulating MCCs had a much longer half-life compared with OC(-)BAP(-) cells, suggesting they belong to a stable cell repertoire. The percentage of MCCs was higher in peripheral blood and bone marrow of type 2 diabetic patients compared with controls but was lowered toward normal levels by optimization of glycemic control. Furthermore, diabetic carotid endoarterectomy specimens showed higher degree of calcification and amounts of cells expressing OC and BAP in the α-smooth muscle actin-negative areas surrounding calcified nodules, where CD68(+) macrophages colocalize. High glucose increased calcification by MCCs in vitro, and hypoxia may regulate MCC generation in vitro and in vivo.
  
  
  CONCLUSIONS
  These data identify a novel type of blood-derived procalcific cells potentially involved in atherosclerotic calcification of diabetic patients.
authors.affiliation: Department of Clinical and Experimental Medicine, Metabolic Division, University of Padova, Medical School, Padova, Italy. gianpaolofadini@hotmail.com
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Fadini
authors.forename: Mattia
authors.initials: M
authors.lastname: Albiero
authors.forename: Lisa
authors.initials: L
authors.lastname: Menegazzo
authors.forename: Elisa
authors.initials: E
authors.lastname: Boscaro
authors.forename: Saula
authors.initials: S
authors.lastname: Vigili de Kreutzenberg
authors.forename: Carlo
authors.initials: C
authors.lastname: Agostini
authors.forename: Anna
authors.initials: A
authors.lastname: Cabrelle
authors.forename: Gianni
authors.initials: G
authors.lastname: Binotto
authors.forename: Marcello
authors.initials: M
authors.lastname: Rattazzi
authors.forename: Elisa
authors.initials: E
authors.lastname: Bertacco
authors.forename: Roberta
authors.initials: R
authors.lastname: Bertorelle
authors.forename: Lorena
authors.initials: L
authors.lastname: Biasini
authors.forename: Monica
authors.initials: M
authors.lastname: Mion
authors.forename: Mario
authors.initials: M
authors.lastname: Plebani
authors.forename: Giulio
authors.initials: G
authors.lastname: Ceolotto
authors.forename: Annalisa
authors.initials: A
authors.lastname: Angelini
authors.forename: Chiara
authors.initials: C
authors.lastname: Castellani
authors.forename: Mirko
authors.initials: M
authors.lastname: Menegolo
authors.forename: Franco
authors.initials: F
authors.lastname: Grego
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Florian
authors.initials: F
authors.lastname: Seeger
authors.forename: Andreas
authors.initials: A
authors.lastname: Zeiher
authors.forename: Antonio
authors.initials: A
authors.lastname: Tiengo
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016025:Bone Transplantation; D002114:Calcinosis / Q000473:pathology*; D002340:Carotid Artery Diseases / Q000473:pathology* / Q000601:surgery; D019070:Cell Lineage / Q000502:physiology; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000473:pathology*; D016894:Endarterectomy, Carotid; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000860:Hypoxia / Q000473:pathology; D007328:Insulin / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D015675:Osteocalcin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D050659:Core Binding Factor Alpha 1 Subunit; D007004:Hypoglycemic Agents; D007328:Insulin; C493709:RUNX2 protein, human; D015675:Osteocalcin; D000469:Alkaline Phosphatase